Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for phe508del cftr

Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR C.E. Wainwright, J.S. Elborn, B.W. Ramsey, G. Marigowda, X. Huang, M. Cipolli, C. Colombo, J.C. Davies, K. De Boeck, P.A. Flume, M.W. Konstan, S.A. McColley, K. McCoy, E.F. McKone, A. Munck, F. Ratjen, S.M. Rowe, D. Waltz, and M.P. Boyle, for the TRAFFIC and TRANSPORT Study Groups* The authors' full names, academic degrees, Cystic fibrosis is a life-limiting disease that is caused by defective or deficient cystic and affiliations are listed in the Appen- fibrosis transmembrane conductance regulator (CFTR) protein activity. Phe508del is dix. Address reprint requests to Dr. Wain-
wright at the Department of Respiratory the most common CFTR mutation.
and Sleep Medicine, Lady Cilento Chil-
dren's Hospital, 501 Stanley St., South METHODS
Brisbane, QLD 4101, Australia, or at We conducted two phase 3, randomized, double-blind, placebo-controlled studies claire . wainwright@ health . qld . gov . au.
that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, * A complete list of the investigators in the in combination with ivacaftor (VX-770), a CFTR potentiator, in patients 12 years TRAFFIC and TRANSPORT studies is pro-vided in the Supplementary Appendix, of age or older who had cystic fibrosis and were homozygous for the Phe508del available at NEJM.org.
CFTR mutation. In both studies, patients were randomly assigned to receive either Drs. Wainwright, Elborn, Ramsey, and lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with Boyle contributed equally to this article.
ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary This article was published on May 17, 2015, end point was the absolute change from baseline in the percentage of predicted and updated on February 4, 2016, at forced expiratory volume in 1 second (FEV ) at week 24.
N Engl J Med 2015;373:220-31.
A total of 1108 patients underwent randomization and received study drug. The mean Copyright 2015 Massachusetts Medical Society. baseline FEV was 61% of the predicted value. In both studies, there were signifi- cant improvements in the primary end point in both lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pul- monary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor–ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor–ivacaftor versus 1.6% among those who received placebo.
CONCLUSIONS
These data show that lumacaftor in combination with ivacaftor provided a benefit
for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.) n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. Lumacaftor with Ivacaftor for Cystic Fibrosis Cystic fibrosis is a genetic disease clinical efficacy in patients who are homozygous that is associated with high rates of pre- for the Phe508del CFTR mutation,19,20 a phase 2 mature death.1-4 It is a multisystem disease study suggested that the combination of luma- that is characterized by pancreatic insufficiency caftor and ivacaftor increased CFTR activity to a and chronic airway infections associated with degree that may be sufficient to improve clinical loss of lung function, repeated pulmonary exacer- outcomes in these patients.21 Therefore, two phase bations, and, ultimately, respiratory failure.5 3 trials (TRAFFIC and TRANSPORT) were con- Cystic fibrosis is caused by gene mutations ducted to evaluate the efficacy and safety of two that result in deficient or dysfunctional cystic different doses of lumacaftor in combination with fibrosis transmembrane conductance regulator ivacaftor in patients with cystic fibrosis who were (CFTR) protein, an anion channel that is normal- homozygous for the Phe508del CFTR mutation.
ly present in the epithelial membrane. Phe508del (c.1521_1523delCTT; formerly F508del) is the most common CFTR mutation; approximately 45% of patients with cystic fibrosis are homozy- Study Design and Oversight
gous for this allele.1 Cystic fibrosis is a progres- The TRAFFIC and TRANSPORT trials were two sive disease; despite advances in therapies de- phase 3, multinational, randomized, double- signed to address the symptoms of the disease, blind, placebo-controlled, parallel-group studies the median predicted survival among patients in which lumacaftor (VX-809, Vertex Pharmaceu- who are homozygous for Phe508del in the United ticals) was orally administered in combination States is 37 years.6 The Phe508del CFTR mutation with ivacaftor (VX-770, Vertex Pharmaceuticals) causes a processing defect that severely reduces for 24 weeks; the studies were conducted from protein levels at the epithelial membrane; for the April 2013 through April 2014. The study design few channels that reach the cell surface, the mu- and methods of data analysis were identical for tation also disrupts channel opening; together, the two studies, with the exception of the inclu- these effects lead to minimal CFTR chloride sion of ambulatory electrocardiography (TRAFFIC transport activity.7-10 One approach to treating only) and adolescent pharmacokinetic assess- cystic fibrosis is to address the underlying cause ments (TRANSPORT only) for a subgroup of pa- of the disease by targeting the CFTR protein tients. The studies were designed to evaluate the dysfunction. Restoring chloride transport to efficacy of lumacaftor–ivacaftor in patients with p.Phe508del CFTR (formerly F508del CFTR) is cystic fibrosis who were homozygous for the therefore thought to require at least two steps: Phe508del CFTR mutation; the evaluation of safety correction of cellular misprocessing to increase was a secondary objective. The protocols (avail- the amount of functional mutated CFTR and able with the full text of this article at NEJM.org) potentiation to further increase channel opening. were reviewed and approved by an ethics com- Lumacaftor is an investigational CFTR cor- mittee at each of the 187 participating centers; rector that has been shown in vitro to correct all patients provided written informed consent.
p.Phe508del CFTR misprocessing and increase Patients were randomly assigned (in a 1:1:1 the amount of cell surface–localized protein.11 ratio) to one of three study groups (Fig. S1 in the Ivacaftor is an approved CFTR potentiator that Supplementary Appendix, available at NEJM.org): increases the open probability of CFTR channels 600 mg of lumacaftor once daily in combination (i.e., the fraction of time that the channels are with 250 mg of ivacaftor every 12 hours (LUM open) in vitro and improves clinical outcomes in [600 mg/day]–IVA), 400 mg of lumacaftor every patients 6 years of age or older who have cystic 12 hours in combination with 250 mg of ivacaftor fibrosis and at least one copy of most class III every 12 hours (LUM [400 mg every 12 hr]–IVA), (gating) mutations.12-17 In vitro studies have shown or lumacaftor-matched placebo every 12 hours that ivacaftor also potentiates surface-localized in combination with ivacaftor-matched placebo p.Phe508del CFTR,18 and the combination of every 12 hours. All regimens were given for 24 lumacaftor with ivacaftor has been associated weeks. Randomization was stratified according with a greater increase in chloride transport to age (<18 years vs. ≥18 years), sex, and pulmo- than has either agent alone.11 nary function (percentage of predicted forced Although neither ivacaftor nor lumacaftor expiratory volume in 1 second [FEV ] at screen- monotherapy has been shown to have meaningful ing, <70 vs. ≥70).
n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. The sponsor of the studies (Vertex Pharma- was assessed, as was the absolute change in ceuticals) designed the protocol in collaboration body weight. The safety of the study regimens with the authors. Site investigators collected the was also evaluated. Subgroup analyses and ad- data, which were analyzed by the sponsor. All ditional assessments of exacerbation, including the authors had full access to the study data assessments of the numbers of patients requir- after the study periods were complete and the ing hospitalization and those requiring treat- data were unblinded. The authors vouch for the ment with intravenous antibiotics, were also accuracy and completeness of the data and for performed.
the fidelity of this report to the study protocols, which are available at NEJM.org.
Statistical Analyses
All patients who underwent randomization and
received at least one dose of study drug were Eligibility criteria included a confirmed diagno- included in the efficacy analysis, in which pa- sis of cystic fibrosis, homozygosity for the Phe- tients were analyzed as part of the study group 508del CFTR mutation, an age of 12 years or to which they were randomly assigned (full older, a percentage of predicted FEV at the time analysis set). In the primary analysis, we evalu- of screening that was 40 to 90% of the predicted ated the treatment difference in the percentage normal values,22,23 and stable cystic fibrosis dis- of predicted FEV at week 24, which was as- ease. Between the screening and baseline visits sessed as the difference between the treatment (≤4 weeks), fluctuation in FEV occurred in some groups and the placebo group in the primary cases and was documented; 81 patients had an end point.
FEV that fell to below 40% of the predicted The safety set included all patients who re- value at baseline. Patients continued to take ceived any amount of study drug; data were ana- their prestudy medications.
lyzed according to the patients' actual study group (regardless of the group to which they had been randomly assigned). The reported adverse All assessments were prespecified in the study events are those that either developed or in- protocols and statistical analysis plans unless creased in severity at or after the time patients otherwise noted. The primary end point was the received the initial dose of study drug, up to 28 absolute change from baseline at week 24 in the days after receipt of the last dose. Additional percentage of predicted FEV , calculated by aver- details regarding the statistical analysis, includ- aging the mean absolute change at week 16 and ing the hierarchical testing procedure for the the mean absolute change at week 24; this ap- multiple end points and the criteria for the as- proach was used because we anticipated that it sessment of statistical significance, are provided would reduce variability, as compared with using in the Supplementary Appendix.
the point estimate at week 24 alone. Key second- ary end points included the relative change from baseline in the percentage of predicted FEV 1 (calculated by averaging the mean values for Participants
weeks 16 and 24), the absolute change from Of the 1122 patients who underwent randomiza- baseline at week 24 in body-mass index (BMI), tion (559 in the TRAFFIC study and 563 in the the absolute change from baseline at week 24 in TRANSPORT study), 1108 received at least one the patient-reported Cystic Fibrosis Question- dose of study drug or placebo (Fig. S2 in the naire–Revised (CFQ-R) respiratory domain score Supplementary Appendix). The baseline demo- (scores range from 0 to 100, with higher scores graphic and other characteristics were well bal- indicating a higher patient-reported quality of anced across study groups (Table 1, and Table S1 life with regard to respiratory status),24 the per- in the Supplementary Appendix). The mean centage of patients with a relative increase from baseline FEV was 61% of the predicted value. At baseline of 5% or higher in the percentage of baseline, a high percentage of patients reported predicted FEV (calculated by averaging the maintenance use of multiple pulmonary, nutri- mean values for weeks 16 and 24), and the num- tional, and other cystic fibrosis therapies. The ber of pulmonary exacerbations through week majority of patients completed their assigned 24. The time to the first pulmonary exacerbation study regimens: 348 patients in the LUM (600 n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. Lumacaftor with Ivacaftor for Cystic Fibrosis Table 1. Baseline Characteristics and Demographic Data.*
LUM (400 mg
LUM (600 mg/day)–IVA
every 12 hr)–IVA
Female sex — no. (%) Mean age (range) — yr Age group — no. (%) Percentage of predicted FEV1 at baseline 60.4 (33.9–99.8) 60.8 (31.1–92.3) 60.5 (31.3–96.5) Subgroup — no. (%) Mean BMI (range)† 21.0 (14.1–32.2) 21.0 (14.2–35.1) 21.5 (14.6–31.4) Maintenance use of pulmonary or respiratory cystic fibrosis therapy at baseline — no. (%) Inhaled antibiotics Inhaled hypertonic saline Inhaled glucocorticoids * The LUM (600 mg/day)–IVA group received 600 mg of lumacaftor (LUM) once daily in combination with 250 mg of ivacaftor (IVA) every 12 hours; the LUM (400 mg every 12 hr)–IVA group received 400 mg of lumacaftor every 12 hours in combination with 250 mg of ivacaftor every 12 hours. FEV1 denotes forced expiratory volume in 1 second.
† The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters.
mg/day)–IVA group (94.6%), 344 patients in the (P<0.001 for all groups) (Table 2). In each study, LUM (400 mg every 12 hr)–IVA group (93.2%), the percentage of patients who had a relative and 362 patients in the placebo group (97.6%).
improvement in the percentage of predicted FEV 1 of 5% or higher was greater in the lumacaftor– ivacaftor groups than in the placebo group In both studies, FEV improvements were ob- (P<0.001 to P = 0.002 for the odds ratio) but was served as early as day 15 and were sustained not significant in the testing hierarchy (Table 2, through 24 weeks in both lumacaftor–ivacaftor and Table S2 in the Supplementary Appendix). In dose groups (Fig. 1A, and Fig. S3 and S4 in the the pooled analysis, approximately twice as Supplementary Appendix). The difference be- many patients in the lumacaftor–ivacaftor tween lumacaftor–ivacaftor and placebo with groups as in the placebo group had a relative respect to the mean absolute change in the per- improvement in the percentage of predicted FEV 1 centage of predicted FEV from baseline at week of 5% or higher (39 to 46% vs. 22%) and 10% or 24 was significant in all dose groups and ranged higher (24 to 27% vs. 13%) (Table 2, and Table from 2.6 to 4.0 percentage points (P<0.001 for S2 and Fig. S5 in the Supplementary Appendix). all comparisons) (Table 2). The difference be- The mean absolute change in the percentage of tween lumacaftor–ivacaftor and placebo with predicted FEV was also assessed in a variety of respect to the mean relative change in FEV was subgroups (e.g., subgroups defined according to also significant and ranged from 4.3 to 6.7% various baseline characteristics and concomitant n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. Figure 1. Absolute Changes from Baseline in the Percent-
A Change from Baseline in Percentage of Predicted FEV1
age of Predicted Forced Expiratory Volume in 1 Second
(FEV1) According to Study Group.
LUM (600 mg/day)–IVA The LUM (600 mg/day)–IVA group received 600 mg of lumacaftor (LUM) once daily in combination with 250 mg of ivacaftor (IVA) every 12 hours; the LUM (400 mg every 12 hr)–IVA group received 400 mg of lumacaftor every 12 hours in combination with 250 mg of ivacaftor LUM (400 mg every 12 hr)–IVA every 12 hours. Panel A shows the mean absolute change in the percentage of predicted FEV of Predicted FEV
1 over time in each study group; the difference between each active-treat- ment group and the placebo group at each time point Absolute Change in Percentage
was significant (P<0.025). Panel B shows subgroup analyses of the differences between the active treat- ment and placebo in the absolute change from baseline in the percentage of predicted FEV1 at week 24. Data in both panels are least-squares means; I bars indicate 95% confidence intervals. The results represent pooled B Subgroup Analysis of the Change from Baseline in Percentage
data from the TRAFFIC and TRANSPORT studies.
of Predicted FEV1
LUM (600 mg/day)–IVA LUM (400 mg every 12 hr)–IVA Difference in Absolute
across all subgroups (Fig. 1B, and Fig. S6 in the Change from Baseline
No. of Patients
Supplementary Appendix). Additional details are provided in the Supplementary Appendix.
Clinically meaningful reductions in the rates of protocol-defined pulmonary exacerbations ≥12 to <18 yr were seen in both lumacaftor–ivacaftor dose groups. The rate ratio (lumacaftor–ivacaftor vs. placebo) ranged from 0.57 to 0.72 (P<0.001 to Percentage of predicted FEV P = 0.05; none of the rate ratios were considered significant in the testing hierarchy) (Table 2, and Table S2 in the Supplementary Appendix). In the pooled analysis, the rate of exacerbations was significantly lower in both lumacaftor–iva- Percentage of predicted FEV1 caftor dose groups than in the placebo group: 30% lower in the LUM (600 mg/day)–IVA group and 39% lower in the LUM (400 mg every 12 hr)– IVA group (P = 0.001 and P<0.001, respectively) (Table 2, and Table S2 in the Supplementary Ap- pendix). Through week 24, the proportion of patients who remained free from exacerbations in the pooled analysis was significantly higher in both lumacaftor–ivacaftor groups than in the Pseudomonas aeruginosa placebo group, and the risk of having an exacer- bation was significantly lower in the luma- caftor–ivacaftor groups (Fig. 2A and Table 2). Additional analyses revealed significant reduc- tions with lumacaftor–ivacaftor therapy in the number of exacerbations leading to hospitaliza- tions and those necessitating the administration of intravenous antibiotics (Fig. 2B).
Over the course of the 24-week period, the mean BMI (the weight in kilograms divided by medications); the improvement in the percentage the square of the height in meters) increased of predicted FEV in the lumacaftor–ivacaftor steadily in both lumacaftor–ivacaftor dose groups versus the placebo group was consistent groups (Fig. S7 in the Supplementary Appendix). n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. Lumacaftor with Ivacaftor for Cystic Fibrosis In the analysis of the individual trials, the differ- tysis (3), bronchospasm (2), dyspnea (2), pulmo- ence between lumacaftor–ivacaftor and placebo nary exacerbation (2), and rash (2). No deaths with respect to the absolute change in BMI was were reported.
significant for both dose groups in the TRANS- The adverse events reported more frequently PORT study but for neither dose group in the in the lumacaftor–ivacaftor groups were gener- TRAFFIC study (Table 2). In the pooled analysis ally respiratory in nature. The majority were of at week 24, the treatment difference versus pla- mild-to-moderate severity and included dyspnea cebo with respect to the absolute change in BMI and chest tightness (Table 3, and Table S3 in the was 0.24 to 0.28 (P<0.001) (Table 2, and Table S2 Supplementary Appendix). Two patients in the and Fig. S7 in the Supplementary Appendix); this placebo group (one with dyspnea and one with represents an improvement of approximately 1% chest discomfort) and four patients in the LUM with lumacaftor–ivacaftor. Across the luma- (600 mg/day)–IVA group (two with dyspnea and caftor–ivacaftor dose groups in TRAFFIC and two with bronchospasm) had adverse events of TRANSPORT, the least-squares mean change respiratory symptoms or reactive airways that from baseline in body weight at week 24 ranged were severe. In patients who had respiratory- from 1.23 to 1.57 kg.
symptom adverse events within 1 to 2 days after The CFQ-R is a cystic fibrosis–specific instru- the initiation of therapy and who did not discon- ment that is designed to evaluate patient-report- tinue the study regimen, the events generally ed assessments of various health-related mea- resolved within the first 2 to 3 weeks of therapy. sures. In both lumacaftor–ivacaftor dose groups, Beyond the first week of therapy, the incidence there were improvements in the within-group of respiratory events was similar in the luma- CFQ-R respiratory domain score; the treatment caftor–ivacaftor and placebo groups. In addi- difference versus placebo was nominally signifi- tion, the pattern of adverse events according to cant (on the basis of the testing hierarchy) in the the severity of lung disease at baseline was analysis of the individual trials only for the LUM generally similar across the groups.
(600 mg/day)–IVA group in the TRAFFIC study; Elevations in levels of alanine or aspartate the treatment difference reached significance in aminotransferase to more than 3 times the up- the LUM (600 mg/day)–IVA group in the pooled per limit of the normal range were observed in analysis (Table 2, and Fig. S8 in the Supplemen- 5.1% of the patients in the placebo group and in tary Appendix).
5.2% of those in the lumacaftor–ivacaftor groups (Table S4 in the Supplementary Appendix). Seri- ous adverse events related to abnormal liver Overall, the proportion of patients reporting function were not observed in the placebo group adverse events was similar across the luma- and were reported for seven patients in the lu- caftor–ivacaftor groups and the placebo group macaftor–ivacaftor groups. After discontinua- (Table 3). Pooled across the studies, serious ad- tion or interruption of lumacaftor–ivacaftor verse events were reported in 28.6% of the pa- therapy, liver function in all patients improved tients in the placebo group and in 17.3 to 22.8% substantially, and results of liver-function tests of the patients in the lumacaftor–ivacaftor returned to baseline in the case of six patients. groups. In all the groups, infective pulmonary Details regarding these events, including con- exacerbation was the most common serious ad- comitant elevations in bilirubin, are provided in verse event (occurring in 24.1% of the patients in the Supplementary Appendix.
the placebo group and in 13.0% of those in the pooled lumacaftor–ivacaftor groups). The pro- portion of patients who discontinued the study regimen because of an adverse event was higher Significant improvements in the percentage of in the lumacaftor–ivacaftor groups than in the predicted FEV were seen in all four lumacaftor– placebo group (4.2% [31 of 738 patients] vs. ivacaftor treatment groups in the TRAFFIC and 1.6% [6 of 370 patients]). Among the patients TRANSPORT studies. In both dose groups in receiving lumacaftor–ivacaftor, the adverse each study, improvements in FEV were seen by events that led to discontinuation of the study day 15 and were sustained throughout the 24- regimen in two or more patients were elevation week study period.
of the creatine kinase level (4 patients), hemop- Lumacaftor–ivacaftor combination therapy n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. absolute baseline absolute baseline from respiratory percentage from baseline† vs. change CFQ-R for ≥5% percentage FEV Efficacy
n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. Lumacaftor with Ivacaftor for Cystic Fibrosis resulted in improvements in multiple clinical end points, and the findings were generally con- sistent across dose groups and studies. Clini- cally important reductions in the rate of pulmo- nary exacerbations were also observed in association with lumacaftor–ivacaftor therapy. Through 24 weeks, the lumacaftor–ivacaftor groups had reductions in the rate of pulmonary exacerbations, with decreases in the numbers of events leading to hospitalization or intravenous antibiotic treatment. FEV and rates of pulmo- nary exacerbations are strong predictors of sur- vival and thus remain important for the evalua- tion of new therapies for cystic fibrosis.25 Significant improvements (i.e., increases) in ment groups and the placebo group, a hierarchical test st and all previous tests was required to claim signifi BMI were observed in the TRANSPORT study and in the pooled analyses but not in the TRAF- FIC study. Across both studies, BMI continued to increase during the study period in both luma- caftor–ivacaftor groups. Although the mecha- nisms for improvement in the nutritional status of patients with cystic fibrosis are not fully de- fined, the gains are hypothesized to reflect ei- ther better caloric absorption, possibly due to normalized intestinal pH,17 or a reduction in energy expenditure resulting from amelioration of lung disease.17,26 Numerical increases in the CFQ-R respiratory domain score favoring active treatment were seen in both dose groups in both studies; however, in the pooled analysis of that score, the treatment difference was significant only in the LUM (600 mg/day)–IVA group and did not meet the requirement for a minimum clinically important difference (4 points).24 It is challenging to interpret these results, given the significant improvements in FEV . The CFQ-R instrument is valuable for assessing patient-re- ported outcomes; however, there is precedent for a lack of correlation with FEV . Studies of tobra- are calculated by averaging the means at weeks 16 and 24.
mycin showed no correlation between changes in CFQ-R and FEV .24 It is also worth noting that the CFQ-R minimum clinically important differ- ence was established as a within-group change in patients who had markers of advanced dis- ease, which complicates its application to other The TRAFFIC and TRANSPORT study cohorts were a population with well-managed cystic fi- brosis, as evidenced by the minimal FEV dete- rioration in the placebo group and the high rates of the use of standard cystic fibrosis therapy. ing procedure was performed to control for multiplicity across primary and key secondary end points; P≤0.0250 in the current te cance in the hierarchy. CFQ-R denotes Cystic Fibrosis Questionnaire–Revised. Changes in the percentage of predicted FEV The difference versus placebo was significant.
* Reported means are least-squares means. For individual studies, within each active-treatment group and between the active-treat † ‡ § The number of pulmonary exacerbations was reported through week 24 and is expressed as a rate per patient over 48 weeks.
The magnitude of the change in FEV was sig- n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. prescribed cystic fibrosis therapies; lumacaftor– A Time to First Pulmonary Exacerbation
ivacaftor is therefore expected to provide a clini- cally meaningful benefit in addition to the standard of care. The determination of the po- tential for lumacaftor–ivacaftor–mediated CFTR modulation to modify the course of disease will require additional analyses and longer-term Although the improvements in FEV associ- ated with lumacaftor–ivacaftor were significant LUM (400 mg every 12 hr)–IVA and consistent with in vitro11 and phase 2 sweat Patients without an Event (%)
LUM (600 mg/day)–IVA chloride and FEV results,21 the effect of luma- caftor–ivacaftor on sweat chloride and FEV was Base- Day
smaller than that observed in patients with the Gly551Asp mutation who were treated with iva- caftor monotherapy.13,14 Whereas CFTR with the B Pulmonary Exacerbations through Wk 24
p.Gly551Asp mutation has a gating defect but is Events Leading to Intravenous
found at the cell surface, CFTR with the p.Phe- 508del mutation has multiple defects, which makes addressing the underlying cause of dis- ease in patients homozygous for this mutation more complex. The most important of these defects is a substantial reduction in processing and transport to the cell surface, plus a reduced stability and channel gating of the few surface- localized proteins. These multiple defects make restoring p.Phe508del CFTR activity and subse- Event Rate per Patient over 48 Wk
quent observation of a clinical benefit more challenging than addressing the p.Gly551Asp gating defect. The smaller changes in sweat chloride and FEV seen in association with luma- caftor–ivacaftor therapy in patients homozygous LUM (600 mg/day)–IVA
LUM (600 mg/day)–IVA
for Phe508del, as compared with the changes LUM (400 mg every 12 hr)–IVA
LUM (400 mg every 12 hr)–IVA
seen in association with ivacaftor monotherapy in patients with Gly551Asp, was predicted in Figure 2. Pulmonary Exacerbations.
vitro and may be due in part to the fact that lu- The time to first pulmonary exacerbation and number of pulmonary exacer- macaftor only partially rescues the p.Phe508del bations leading to hospitalization or treatment with intravenous antibiotics CFTR processing defect,11 which results in fewer are shown. In Panel B, the number of pulmonary exacerbations observed p.Phe508del CFTR channels at the cell surface through week 24 is expressed as a rate per patient over 48 weeks. The re- than are seen with p.Gly551Asp CFTR.
sults represent pooled data from the TRAFFIC and TRANSPORT studies.
Two in vitro studies have suggested that treatment (for ≤48 hours) with potentiators, in- nificant and was in the range of the magnitudes cluding ivacaftor, may reduce the stability and of change seen in studies of other cystic fibrosis expression of corrected p.Phe508del.32,33 Al- therapeutics.27-31 The changes due to treatment though it is possible that ivacaftor affects the in the percentage of predicted FEV were largely steady-state levels of corrected p.Phe508del consistent across studies, dose groups, and all CFTR in vitro, the results of the TRAFFIC and subgroups analyzed, including subgroups de- TRANSPORT studies, which included more than fined according to age, baseline FEV (<40 vs. 1100 patients, suggest that lumacaftor–ivacaftor ≥40), and status with respect to Pseudomonas ae- provides a clinical benefit that is greater than ruginosa infection. Improvements in FEV and that previously observed with either agent BMI and reductions in exacerbations were ob- alone.20,21 Moreover, the clinical benefit was sus- served while patients continued to use their tained for the entire duration of the studies. n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. Lumacaftor with Ivacaftor for Cystic Fibrosis Table 3. Adverse Events Associated with the Study Regimens.*
LUM (400 mg
LUM (600 mg/day)–IVA
every 12 hr)–IVA
number of patients (percent) Any adverse event reported Discontinuation of the study regimen because of an adverse event At least one serious adverse event Most common adverse events† Infective pulmonary exacerbation of Increase in sputum production Abnormal respiration (chest tight- Oropharyngeal pain Upper respiratory tract infection Serious adverse events occurring in at least 3 patients in any treatment group Infective pulmonary exacerbation of Distal intestinal obstruction syndrome * The reported adverse events are those that either developed or increased in severity at or after the time patients re- ceived the initial dose of study drug (placebo or active agent), up to 28 days after receipt of the last dose.
† The most common adverse events were defined as those that occurred in at least 10% of patients in any treatment group.
Nevertheless, the differences between the results tightness were reported more frequently in the of treatment with lumacaftor–ivacaftor in pa- active-treatment groups. In a phase 2 study, tients with the Phe508del mutation and treat- treatment with lumacaftor monotherapy was as- ment with ivacaftor in patients with the sociated with an initial increased risk of dyspnea Gly551Asp mutation point to the need for con- or chest tightness, although these symptoms tinued development of CFTR modulators that were uncommon after the addition of ivacaftor will further improve on the meaningful FEV to lumacaftor.21 Elevated levels of liver enzymes benefits observed in the TRAFFIC and TRANS- were observed in a similar number of patients in PORT studies.
the active-treatment groups and the placebo Lumacaftor–ivacaftor therapy at both dosing group; however, serious adverse events related to regimens generally had an acceptable side-effect elevation of liver enzymes were reported only in profile. The proportion of patients who discon- the active-treatment group.
tinued the study regimen for reasons related to The TRAFFIC and TRANSPORT studies includ- an adverse event was higher among those who ed the same two doses of lumacaftor so that we received lumacaftor–ivacaftor than among those could ascertain whether there was a dose response who received placebo, and dyspnea and chest for the CFTR corrector. Pooled across the two n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. studies, the dose regimens appeared to have simi- reports receiving grant support from Achaogen, Apartia, Bayer lar efficacy and safety profiles, with no clear dif- Healthcare, Breathe Easy, Bristol-Myers Squibb, Catabasis, 12th Man Technologies, Caltaxsys, Corbus Pharmaceuticals, Corner- ferentiation except with respect to pulmonary ex- stone Therapeutics, CSL Behring, CURx Pharmaceuticals, Eli Lilly, acerbation–related outcomes, which consistently Flatley Discovery Lab, Genentech, Gilead Sciences, GlycoMimetics, favored the LUM (400 mg every 12 hr)–IVA group. Grifols Therapeutics, INC Research, Insmed, KaloBios, Kamada, Mpex Pharmaceuticals, N30 Pharmaceuticals, Nordmark, Novar- In conclusion, in the TRAFFIC and TRANSPORT tis, Parion Sciences, Pharmagenesis (Cornerstone 281), Phar- studies, lumacaftor in combination with ivacaftor maxis, ProQR Therapeutics, Pulmatrix, PulmoFlow, Respira improved FEV and reduced the rate of pulmo- Therapeutics, Savara Pharmaceuticals, and Vertex. Dr. Colombo reports receiving fees for serving on advisory boards from Vertex. nary exacerbations in patients with cystic fibro- Dr. Davies reports receiving fees through her institution for sis who were homozygous for the Phe508del serving on advisory boards for Vertex, Proteostasis, Novartis, CFTR mutation. Lumacaftor–ivacaftor therapy and Gilead; she has also received fees through her institution from Vertex for participation in educational activities and acting generally had an acceptable side-effect profile, as lead investigator in other trials. Dr. De Boeck reports receiv- with more than 93% of patients completing the ing fees for serving on an advisory board from Pharmaxis and assigned therapy regimen. These data show that KaloBios, fees for serving on a data monitoring committee from Aptalis, and consulting fees from Ablynx, Galapagos, Gilead, the combination of a CFTR corrector and poten- PTC Therapeutics, Celtaxys, and Boehringer Ingelheim; she has tiator, designed to address the underlying cause also served as principal investigator in studies funded by Gilead, of cystic fibrosis by targeting CFTR, can benefit Pharmaxis, and PTC Therapeutics. Dr. Flume reports receiving consulting fees and grant support from Vertex. Dr. Konstan re- patients who are homozygous for the Phe508del ports receiving fees for serving on advisory boards from Genen- CFTR mutation and represents a treatment mile- tech, Gilead Sciences, Insmed, and Savara Pharmaceuticals, con- stone for the 45% of patients with cystic fibrosis sulting fees from Digestive Care, Novartis, PTC Therapeutics, Chiesi, KaloBios, and Celtaxsys, lecture fees from Novartis, who are homozygous for this mutation.
travel support from Genentech, Gilead Sciences, Insmed, Novartis, Supported by Vertex Pharmaceuticals; a program grant from PTC Therapeutics, and Celtaxsys, and grant support through his the Children's Hospital Foundation, Brisbane, Queensland, institution from Genentech, Insmed, Novartis, PTC Therapeu- Australia (to Dr. Wainwright); the Northern Ireland Clinical tics, Savara Pharmaceuticals, and KaloBios. Dr. McCoy reports Research Network (Respiratory Health) in Belfast Health and receiving travel support from Novartis and Pharmaxis, and grant Social Care Trust (to Dr. Elborn); grants from the Institute of support through her institution from Aptalis, KaloBios, Novartis, Translational Health Sciences, National Institutes of Health Gilead Sciences, Pharmaxis, Savara Pharmaceuticals, Genen- (NIH) (UL1TR000423) and the Cystic Fibrosis Translational tech, AbbVie, Janssen, and N30 Pharmceuticals. Dr. McKone re- Research Center, NIH (P30DK089507, both to Dr. Ramsey); the ports receiving fees for serving on advisory boards from Novartis National Institute for Health Research Respiratory Biomedical and Vertex, consulting fees from Vertex, lecture fees from Gilead Research Unit at the Royal Brompton and Harefield NHS Founda- Sciences, travel support from Gilead Sciences and Novartis, and tion Trust and Imperial College London (to Dr. Davies); the South grant support from Vertex. Dr. Munck reports receiving fees for Carolina Clinical and Translational Research Institute, Medical serving on advisory boards from Novartis. Dr. Ratjen reports University of South Carolina (UL1TR000062 to Dr. Flume); the receiving consulting fees from Bayer, Talecris, CSL Behring, Clinical and Translational Science Collaborative of Cleveland Roche, Gilead Sciences, Genentech, and KaloBios, travel support (UL1TR000439), a grant from the Cystic Fibrosis Core Center from PARI Pharma, and grant support from Novartis. Dr. Rowe (DK027651), and a grant from the Cystic Fibrosis Foundation reports receiving grant support from Vertex, PTC Therapeutics, Therapeutics Development Network to Case Western Reserve Novartis, and the Forest Research Institute. Dr. Boyle reports University School of Medicine (all to Dr. Konstan); grants from receiving fees for serving on advisory boards for Savara Pharma- the Northwestern University Clinical and Translational Sciences ceuticals, Vertex, Genentech, and Novartis. Dr. Marigowda, Dr. Institute (UL1RR025741) and the Cystic Fibrosis Foundation Huang, and Dr. Waltz are employees of and hold stock or stock Therapeutics Development Network (MCCOLL14YO) (both to Dr. options in Vertex. No other potential conflict of interest relevant McColley); grants from the UAB Center for Clinical and Transla- to this article was reported.
tional Science (UL1TR000165), the UAB Cystic Fibrosis Research Disclosure forms provided by the authors are available with Center (DK072482), and the Cystic Fibrosis Foundation (all to the full text of this article at NEJM.org.
Dr. Rowe); and the Johns Hopkins Institute for Clinical and We thank all the patients, study coordinators, and study in- Translational Research, which is funded in part by a grant from vestigators; members of the Cystic Fibrosis Foundation, the the NIH (UL1TR001079, to Dr. Boyle).
United States Cystic Fibrosis Foundation Therapeutics Develop- Dr. Wainwright reports receiving consulting fees from Med- ment Network, the European Clinical Trials Network, and the scape and Vertex, lecture fees and travel support from Vertex Cystic Fibrosis Foundation Data and Safety Monitoring Board and Novartis, grant support from Vertex, GlaxoSmithKline, and for their support of this trial; Elizabeth Dorn, Ph.D. (Vertex Novo Nordisk, and fees on a per patient basis as principal investi- Pharmaceuticals), for providing medical writing, editorial, and gator of a clinical study from Boehringer Ingelheim. Dr. Ramsey coordination support; and Jonathan Kirk (Vertex Pharmaceuti- cals) for providing graphic design support.
The authors' full names and academic degrees are as follows: Claire E. Wainwright, M.B., B.S., M.D., J. Stuart Elborn, M.D., Bonnie W. Ramsey, M.D., Gautham Marigowda, M.D., Xiaohong Huang, Ph.D., Marco Cipolli, M.D., Carla Colombo, M.D., Jane C. Davies, M.D., Kris De Boeck, M.D., Patrick A. Flume, M.D., Michael W. Konstan, M.D., Susanna A. McColley, M.D., Karen McCoy, M.D., Edward F. McKone, M.D., Anne Munck, M.D., Felix Ratjen, M.D., Steven M. Rowe, M.D., M.S.P.H., David Waltz, M.D., and Michael P. Boyle, M.D., for the TRAFFIC and TRANSPORT Study Groups.
The authors' affiliations are as follows: Queensland Children's Medical Research Institute, Royal Children's Hospital, Lady Cilento Children's Hospital, and University of Queensland School of Medicine, Brisbane, Australia (C.E.W.); Queens University of Belfast, Belfast (J.S.E.), and Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London (J.C.D.) — all in the n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved. Lumacaftor with Ivacaftor for Cystic Fibrosis United Kingdom; Seattle Children's Hospital and University of Washington School of Medicine, Seattle (B.W.R.); Vertex Pharmaceuti- cals, Boston (G.M., X.H., D.W.); Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona (M.C.), and Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan (C.C.) — both in Italy; University Hospital Gasthuisberg, Leuven, Belgium (K.D.B.); Medical University of South Carolina, Charleston (P.A.F.); Case Western Reserve University School of Medi- cine, Rainbow Babies and Children's Hospital, Cleveland (M.W.K.), and the Department of Pediatrics, Pulmonary Division, Nationwide Children's Hospital and Ohio State University, Columbus (K.M.) — both in Ohio; Stanley Manne Children's Research Institute, North- western University Feinberg School of Medicine, Chicago (S.A.M.); St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin (E.F.M.); Hôpital Robert Debré, Paediatric Gastroenterology and Respiratory Department, CF Center, As- sistance Publique–Hôpitaux de Paris, Université Paris 7, Paris (A.M.); Division of Respiratory Medicine, Department of Pediatrics, Physiology, and Experimental Medicine, Hospital for Sick Children, University of Toronto, Toronto (F.R.); University of Alabama at Birmingham, Birmingham (S.M.R.); and Johns Hopkins Medicine, Baltimore (M.P.B.).
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protein processing defect in vitro by the KB. Spirometric reference values from a Copyright 2015 Massachusetts Medical Society. n engl j med 373;3 nejm.org July 16, 2015 The New England Journal of Medicine Downloaded from nejm.org on March 29, 2016. For personal use only. No other uses without permission. Copyright 2015 Massachusetts Medical Society. All rights reserved.

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